This proposal is a resubmission of a competing renewal application for an ongoing collaborative program among investigators at the Massachusetts Institute of Technology, New England Eye Center and University of Pittsburgh Medical Center Eye Center. This is a multidisciplinary program which integrates imaging technology research, clinical and small animal imaging studies. The specific aims are: Aim 1. Next generation OCT technology and methods for structural and functional imaging. We propose to develop ultrahigh speed swept source OCT (SSOCT) at 1050nm which will enable wide field volumetric retinal and choroidal structural imaging, OCT angiography of retinal and choroidal microvasculature as well as Doppler OCT to measure total retinal blood flow and functional stimulus response. In parallel, we will continue development of ultrahigh resolution (UHR) spectral domain OCT (SDOCT) with 2-3?m axial resolution to visualize and measure outer retinal structures. We will also develop 3D image processing techniques to correct motion artifacts, enable volumetric data averaging and quantitatively analyze 3D data. Volumetric data from different patient visits will be registered to track disease progression and measure subtle changes in pathology. Aim 2. Structural and functional imaging of age-related macular degeneration (AMD), diabetic retinopathy (DR) and glaucoma. Cross sectional and longitudinal structural and functional clinical imaging studies will be performed in patients with AMD, DR and glaucoma. Changes in photoreceptors, RPE and Bruch's membrane are possible markers of disease in AMD and will be investigated using UHR SDOCT. Volumetric structural imaging of the retina and choroid will be performed using ultrahigh speed SSOCT. 3D vascular and capillary structure in the retina, ONH, choriocapillaris and choroid, potential markers of AMD, DR, and glaucoma will be investigated using OCT angiography. Alterations in blood flow and functional flicker stimulus response (neurovascular coupling) will be investigated in DR and glaucoma patients using Doppler OCT and OCT angiography. Studies will include patients with different levels of disease as well as normal controls. The objective is to identify new structural and functional markers for early diagnosis, monitoring progression and response to therapy. Aim 3. New OCT techniques for structural and functional imaging in small animals. We propose to develop ultrahigh speed OCT methods for structural and functional hemodynamic imaging in small animals. Studies will investigate the streptozotocin-induced rat diabetes model compared to normal controls. We will also develop spectroscopic OCT techniques to measure retinal vascular permeability with Evans blue dye exogenous contrast. Spectroscopic OCT will provide 3D maps of retinal vascular permeability and will be more efficient than current ex vivo Evans blue vascular permeability assays. Advances in small animal imaging will be powerful tools for both fundamental studies of disease mechanisms and pharmaceutical development.